JP2021178848A - Suspension formulations of insulinotropic peptides and uses thereof - Google Patents

Abstract

To provide a suspension formulation of an insulinotropic peptide (e.g., glucagon-like peptide-1 (GLP-1) or exenatide).SOLUTION: The suspension formulation comprises (i) a non-aqueous, single-phase vehicle, comprising one or more polymers and one or more solvents, where the vehicle exhibits viscous fluid characteristics, and (ii) a particle formulation comprising the insulinotropic peptide dispersed in the vehicle. The particle formulation further includes a stabilizing component comprising one or more stabilizers, for example, carbohydrates, antioxidants, amino acids, buffers and the like. Devices for delivering the suspension formulations and methods of use are also described.SELECTED DRAWING: Figure 3

Description

Cross-references to related applications This application is in the interest of US Provisional Application No. 60 / 926,005 filed April 23, 2007 and US Provisional Application No. 61 / 072,202 filed May 28, 2008. All of these applications are incorporated herein by reference.

Technical Field The present invention relates to organic chemistry, pharmaceutical chemistry, and peptide chemistry applied to pharmaceutical research and development. Aspects of the invention provide suspension formulations of insulin secretagogue peptides for use in mammals and for the treatment of diseases or conditions.

Background of the Invention Glucagon-like peptide-1 (GLP-1) is one of the important hormones and is a fragment of the human proglucagon molecule. GLP-1 is rapidly metabolized by peptidase (dipeptidyl peptidase IV or DPP-IV). A fragment of GLP-1, glucagon-like peptide-1 (7-36) amide (glucagon-like insulin secretagogue peptide, or GLIP) is a gastrointestinal peptide that promotes insulin release at physiological concentrations (Gutniak M. , et al., N Engl J Med. 1992 May 14; 326 (20): 1316-22). GLP-1 and GLP-1 (7-36) amides are incretins. Incretins are gastrointestinal hormones that cause an increase in the amount of insulin released from beta cells after a meal.

Eating, as well as stimulating the sympathetic nervous system, stimulates GLP-1 secretion in the mammalian small intestine. In addition, GLP-1 stimulates insulin production and secretion, somatostatin release, glucose utilization by increased insulin sensitivity, and, in mammalian studies, also stimulates beta cell function and proliferation.

GLP-1 (7-36) amide and GLP-1 (7-37) normalize fasting hyperglycemia in patients with type 2 diabetes (Nauck, MA, et al., Diabet. Med. 15 (11)) : 937-45 (1998)).

Exendin-4 is an incretin mimetic purified from the Heloderma suspectum venom (ie, it mimics the physiological effects of incretins) (Eng, J., et al., J. Biol. Chem. 267: 7402-05 (1992)), and its structural association with the incretin hormone GLP-1 (7-36) amide. Exendin-4 and abbreviated exendin- (9-39) amides specifically interact with GLP-1 receptors on insulinoma-derived cells and lung cell membranes (Goke R, et al., J Biol). Chem. 268: 19650-55 (1993)). Exendin-4 has approximately 53% homology with human GLP-1 (Pohl, M., et al., J Biol Chem. 273: 9778-84 (1998)). However, unlike GLP-1, exendin-4 is resistant to degradation by DPP-IV. Glycine confers resistance to degradation by DPP-IV (Young, A.A., et al., Diabetes 48 (5): 1026-34 (1999)).

Outline of the Invention The present invention relates to a suspension preparation composition containing a particle preparation and a suspension vehicle, an apparatus containing such a formulation, a method for making such a formulation and an apparatus, and a method for using them.

In one aspect, the invention comprises a suspension comprising an insulin secretagogue peptide and one or more stabilizers selected from the group consisting of sugars, antioxidants, amino acids, buffers, and inorganic compounds. Regarding the formulation. The suspension composition further comprises a non-aqueous single-phase suspension vehicle comprising one or more polymers and one or more solvents. The suspended vehicle has viscous fluid properties, and the particle formulation is dispersed in the vehicle.

In one embodiment, the suspension formulation comprises a particle formulation comprising an insulin secretagogue peptide, a disaccharide (eg, sucrose), methionine, and a buffer (eg, citrate), and one or more pyrrolidone polymers (eg, polyvinylpyrrolidone). ) And a non-aqueous single-phase suspension vehicle containing one or more solvents (eg, lauryl lactate, lauryl alcohol, benzyl benzoate, or a mixture thereof).

Examples of insulin secretagogue peptides include, but are not limited to, glucagon-like peptide-1 (GLP-1), exenatide, and derivatives or analogs thereof. In one embodiment of the invention, the insulin secretagogue peptide is a GLP-1 (7-36) amide. In another aspect of the invention, the insulin secretagogue peptide is exenatide.

The particle preparation according to the present invention may further contain a buffer selected from the group consisting of, for example, citrate, histidine, succinate, and mixtures thereof.

The particle preparation according to the present invention is, for example, a group consisting of citrate, histidine, succinate, and a mixture thereof, NaCl, Na ₂ SO ₄ , י ₃ , KCl, KH ₂ PO ₄ , CaCl ₂ , and MgCl _2. It may further contain an inorganic compound selected from.

One or more stabilizers in the particle preparation may include, for example, sugar selected from the group consisting of lactose, sucrose, trehalose, mannitol, cellobiose, and mixtures thereof.

One or more stabilizers in the particle formulation include, for example, methionine, ascorbic acid, sodium thiosulfate, ethylenediaminetetraacetic acid (EDTA), citric acid, cysteine, thioglycerol, thioglycolic acid, thiosorbitol, butylated hydroxyanisole, And propyl ascorbic acid, and antioxidants selected from the group consisting of mixtures thereof and the like.

One or more stabilizers in the particle formulation may contain amino acids.

In one embodiment, the solvent for the suspended vehicle according to the present invention is selected from the group consisting of lauryl lactate, lauryl alcohol, benzyl benzoate, and mixtures thereof. An example of a polymer capable of formulating the suspended vehicle is pyrrolidone (eg, polyvinylpyrrolidone). In one preferred embodiment, the polymer is pyrrolidone and the solvent is benzyl benzoate.

The suspension formulation typically has an overall moisture content of less than about 10 wt% and, in one preferred embodiment, less than about 5 wt%.

A transplantable drug delivery device can be used to contain and deliver the suspended formulations according to the invention. In one embodiment, the device can be an osmotic delivery device.

Suspension formulations according to the invention can be used to treat any of the many medical conditions or conditions in a subject in need of treatment, such as type II diabetes. In one embodiment, the implantable drug delivery device delivers the suspension formulation according to the invention at a substantially uniform rate for a period of about 1 month to about 1 year. The device can be subcutaneously implanted, for example, in a convenient location.

The present invention also includes the method for producing a suspension preparation, a particle preparation, a suspension vehicle, and an apparatus according to the present invention, which are described in the present invention.

These and other aspects of the invention can be readily conceived by one of ordinary skill in the art in light of the disclosure herein.

The sequences of two examples of insulin-secreting peptides are shown: FIG. 1A shows the glucagon-like peptide 1 (7-36) amide (GLP-1 (7-36) amide) (SEQ ID NO: 1), and FIG. 1B represents a synthetic exenatide peptide (SEQ ID NO: 2). The sequences of two examples of insulin-secreting peptides are shown: FIG. 1A shows the glucagon-like peptide 1 (7-36) amide (GLP-1 (7-36) amide) (SEQ ID NO: 1), and FIG. 1B represents a synthetic exenatide peptide (SEQ ID NO: 2).

DUROS® (ALZA Corporation, Mountain View CA is the right holder and licensed to Intarcia Therapeutics, Inc., Hayward CA) Test animals treated with sustained delivery of exenatide from the device. The data of the average weight of is shown. In this figure, the vertical axis is the average weight in grams (body weight (g)), and the horizontal axis is the number of days (days). The obese animals in group 1 (black diamonds) were in the control group receiving 0 mcg of exenatide daily from the DUROS® device. The animals in group 2 (black squares) were obese animals receiving 20 mcg of exenatide daily from the DUROS® device. The animals in group 3 (black-painted triangles) were lean animals receiving 20 mcg of exenatide daily.

The data of the mean blood glucose concentration of the test animal group treated by the continuous delivery of exenatide from the DUROS® apparatus are shown. In this figure, the vertical axis is the average blood glucose in mg / dL units (blood glucose (mg / dL)), and the horizontal axis is the number of days (days). Here, each day has three associated blood glucose levels (A, B, C). Day 1A is the fasting blood glucose level, and Day 8A is the fasting blood glucose level. Obese animals in group 1 (black diamonds) were in the control group receiving 0 mcg of exenatide per day. The animals in group 2 (black squares) were obese animals receiving 20 mcg of exenatide daily from the DUROS® device. The animals in Group 3 (black-painted triangles) were slimming animals receiving 20 mcg of exenatide daily from the DUROS® device.

The data of the mean HbA1c value of the test animal group treated by the continuous delivery of exenatide from the DUROS® apparatus is shown. In this figure, the vertical axis is the average percentage HbA1c (HbA1c (%)), and the horizontal axis is the number of days (days). The obese animal group in group 1 (black-painted rhombus) was a control group in which exenatide was administered at 0 mcg per day. The animals in group 2 (black squares) were obese animals receiving 20 mcg of exenatide per day. The animals in Group 3 (black-painted triangles) were lean animals receiving 20 mcg of exenatide daily from the DUROS® device.

Detailed Description of the Invention All patents, publications, and patent applications cited herein are incorporated by reference in their respective individual patents, publications, or patent applications for all purposes herein. Incorporated by reference herein, as specifically and individually indicated to be.

1.0.0 Definitions It should be understood that the terminology used herein is for the sole purpose of describing specific embodiments and is not intended to be limiting. As used herein and in the appended claims, the singular forms "a", "an" and "the" are other indications in the context. Includes multiple objects unless there is. Thus, for example, a reference to "a solvent" includes a combination of two or more such solvents, and a reference to "a peptide" includes one or more peptides, a mixture of a plurality of peptides, and the like.

Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention relates. Other methods and materials similar to or equivalent to those described herein may be used in the practice of the invention, although preferred materials and methods are described herein.

When describing and referring to the invention, the following terminology may be used according to the definitions set below.

The terms "peptide", "polypeptide", and "protein" are used herein as substitutables, and typically two or more amino acids (eg, most typically L). -Amino acids, but refers to molecules containing chains of, for example, D-amino acids, modified amino acids, amino acid analogs, and / or amino acid mimetics. Peptides are functionally added, for example, through post-translational modifications. It may include an additional group that modifies the chain of the amino acid, such as a group. Examples of this translation modification include, but are not limited to, acetylation, alkylation (including methylation), biotination, glutamilation, glycyl. Includes conjugation, glycosylation, isoprenylation, lipoylation, phosphopantetinylation, phosphorylation, selenation, and C-terminal amidation. The term peptide also includes amino-terminated and / or carboxy-terminated. Modifications of the terminal amino group include, but are not limited to, des-amino, N-lower alkyl, N-di-lower alkyl, and N-acyl modification of the terminal carboxyl group. Modifications include, but are not limited to, amides, lower alkyl amides, dialkyl amides, and lower alkyl ester modifications (eg, C _{1 to} C ₄ alkyl as lower alkyl).

One terminal amino acid of the peptide chain typically has a free amino group (ie, the amino terminal). The other terminal amino acid of the chain typically has a free carboxyl group (ie, the carboxy end). Typically, the amino acids that form a peptide are numbered starting at the amino terminus of the peptide and increasing towards the carboxy terminus.

As used herein, the term "amino acid residue" refers to an amino acid that is incorporated into a peptide by amide bond or amide bond mimetic.

As used herein, the term "insulin-promoting" refers to the ability of a compound (eg, an insulin-promoting hormone), such as a peptide, to stimulate or influence insulin production and / or activity. Such compounds typically stimulate the secretion or biosynthesis of insulin in the subject.

As used herein, the term "insulin secretagogue peptide" is, but is not limited to, glucagon-like peptide 1 (GLP-1) or its derivatives and analogs, as well as exenatide or its derivatives and similar. Including the body.

As used herein, the term "vehicle" refers to the medium used to carry a compound. Vehicles according to the invention typically include compounds such as polymers and solvents. Suspension vehicles according to the present invention typically include solvents and polymers used to prepare suspension formulations of polypeptide particles.

As used herein, the term "phase separation" refers to a plurality of phases (eg, a liquid or gel phase) in a suspended vehicle, such as when the suspended vehicle is in contact with an aqueous environment. ) Refers to the formation. In some embodiments of the invention, the suspended vehicle is formulated to exhibit phase separation upon contact with an aqueous environment having less than about 10% water.

As used herein, the term "single-phase" refers to a uniform system of solid, semi-solid, or liquid that is physically and chemically uniform throughout.

As used herein, the term "dispersed" means that a compound, eg, a peptide, is dissolved, dispersed, suspended, or otherwise partitioned in a suspended vehicle. Refers to distributing.

As used herein, the term "chemically stable" is used in a pharmaceutical product within a given time by a chemical pathway such as deamidation (usually by hydrolysis), aggregation, or oxidation. It means that the formation of decomposition products produced in Japan is in an acceptable percentage.

As used herein, the term "physically stable" is in the permissible percentage of aggregate formation (eg, dimers and other high molecular weight products) in a pharmaceutical product. Point to that. Furthermore, a physically stable pharmaceutical product does not change its physical state, for example, from liquid to solid, or from amorphous to crystalline form.

As used herein, the term "viscosity" is a value determined from the ratio of shear rate to shear stress (eg, Considine, DM & Considine, GD, Encyclopedia of Chemistry, 4th Edition, Van Nostrand, Refer to Reinhold, NY, 1984), which is essentially required as follows:

F / A = μ * V / L (equation 1)
[During the ceremony,
F / A = shear stress (force per unit area)
μ = Proportional constant (viscosity)
V / L = Velocity per layer thickness (shear velocity)]

From this relationship, the ratio of shear rate to shear stress defines viscosity. Measurements of shear stress and shear rate are typically determined using parallel plate rheometery performed under selected conditions (eg, temperature 37 ° C.). Other methods for determining viscosity include measuring kinematic viscosity using a viscometer such as the Cannon-Fenske viscometer for Canon-Fenske opaque solutions, or an Ostwald viscometer. included. In general, the suspended vehicle according to the invention is sufficiently viscous to prevent the suspended particle product from precipitating during storage or use in a method of delivery, for example by a implantable drug delivery device. Have.

As used herein, the term "non-aqueous" means that the overall moisture content of, for example, a suspension formulation is typically about 10 wt% or less, preferably 5 wt% or less, and more preferably 4 wt%. Indicates that it is less than.

As used herein, the term "subject" refers to, but is not limited to, members of any chordate subphylum, humans, and non-human primates such as red-tailed monkeys, chimpanzees and other apes and monkeys. Other primates, including species; livestock such as cows, sheep, pigs, goats and horses; pets such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs; chickens, chimpanzees and other poultry , Duck, geese and other poultry, wild birds, and hunting birds. The term does not refer to a particular age. It is intended to extend to both adults and newborns.

The terms "drug," "therapeutic agent," and "beneficial agent" are used interchangeably to refer to any therapeutically active compound that is delivered to a subject to produce the desired beneficial effect. NS. In one embodiment of the invention, the drug is an insulin secretagogue peptide such as, for example, GLP-1, exenatide, and derivatives or analogs thereof. The devices and methods according to the present invention are suitable for delivery of polypeptides and small molecules, as well as combinations thereof.

As used herein, "osmotic delivery device" refers to a device for delivering one or more beneficial agents (eg, an insulin secretagogue peptide) to a subject, which device is, for example, suspension. Includes formulations (eg, containing insulin secretagogue peptides) and containers with a lumen containing penetrant formulations (eg, made of titanium alloys) and the like. The piston component located in the lumen isolates the suspension from the penetrant. A semipermeable membrane is located at the first distal end of the container adjacent to the penetrant, and a flow modulator (the suspension is said) at the second distal end of the container adjacent to the suspension. (Defines the delivery orifice) through which the device escapes is located. Typically, the osmotic delivery device is implanted within the subject, eg, subcutaneously (eg, medial, lateral or dorsal of the upper arm; or abdomen).

2.0.0 Summary of the Invention Before describing the present invention in detail, the present invention describes a specific type of drug delivery, a specific type of drug delivery device, a specific peptide source, a specific solvent, a specific polymer, etc. Please understand that it is not limited to. This is because the use of such particular material may be selected in view of the teachings of the present invention. It should also be understood that the techniques used herein are solely for the purpose of describing particular aspects of the invention and are not intended to be limiting.

In one embodiment, the invention relates to a suspension composition comprising a particle formulation and a suspension vehicle. The particle formulation comprises, but is not limited to, an insulin secretagogue peptide and one or more stabilizers. The one or more stabilizers are typically selected from the group consisting of sugars, antioxidants, amino acids, and buffers. The suspension vehicle is typically a non-aqueous single-phase suspension vehicle containing one or more polymers and one or more solvents. The suspended vehicle exhibits viscous fluid properties. The particle product is uniformly dispersed in the vehicle.

In one embodiment of the invention, the insulin secretagogue is a glucagon-like peptide-1 (GLP-1), a derivative of GLP-1 (eg, GLP-1 (7-36) amide), or GLP-1. It is an analog.

In another aspect of the invention, the insulin secretagogue peptide is exenatide, a derivative of exenatide, or an analog of exenatide.

A particular aspect of the invention is typically one or more of the following stabilizers: one or more sugars (eg, disaccharides such as lactose, sucrose, trehalose, cellobiose, and mixtures thereof, etc.); One or more antioxidants (eg, methionine, ascorbic acid, sodium thiosulfate, ethylenediamine tetraacetic acid (EDTA), citric acid, butylhydroxytoluene, and mixtures thereof); and one or more buffers (eg, quen). Includes acid salts, histidine, succinate, and combinations thereof). In one preferred embodiment, the particle preparation comprises an insulin secretagogue peptide, sucrose, methionine, and a citrate buffer. The ratio of insulin secretagogue peptide to sucrose + methionine is typically about 1/20, about 1/10, about 1/5, about 1/2, about 5/1, about 10/1, or about. It is 20/1, preferably between about 1/5 and 5/1, and more preferably between about 1/3 and 3/1. The particle preparation is preferably a particle preparation prepared by spray drying, and has a low water content, preferably 10 wt% or less, and more preferably 5 wt% or less. In another embodiment, the particle formulation can be lyophilized.

Suspended vehicles according to the present invention include one or more solvents and one or more polymers. Preferably, the solvent is selected from the group consisting of lauryl lactate, lauryl alcohol, benzyl benzoate, and mixtures thereof. More preferably, the solvent is lauryl lactate or benzyl benzoate. Preferably, the polymer is pyrrolidone. In some embodiments, the polymer is polyvinylpyrrolidone (eg, polyvinylpyrrolidone K-17, which typically has an average molecular weight in the range of approximately 7,900 to 10,800). In one embodiment of the invention, the solvent essentially comprises benzyl benzoate and polyvinylpyrrolidone.

The suspension is typically low in overall water content, eg, about 10 wt% or less, and in one preferred embodiment, about 5 wt% or less.

In another aspect, the invention relates to a implantable drug delivery device comprising a suspension formulation according to the invention. In a preferred embodiment, the drug delivery device is an osmotic delivery device.

The present invention further includes a suspension preparation according to the present invention and a method for producing an osmotic delivery device filled with the suspension preparation according to the present invention. In one embodiment, the invention comprises a method of making an osmotic delivery device comprising filling a container inside the osmotic delivery device with a suspension formulation.

In another aspect, the invention comprises delivering a suspension formulation according to the invention from an osmotic delivery device at a substantially uniform rate, including diabetes in a subject requiring such treatment (eg, type 2). It relates to a method for treating diabetes (diabetes mellitus or gestational diabetes mellitus). Typically, the suspension is delivered for a period of about 1 month to about 1 year, preferably about 3 months to about 1 year. The method may further include subcutaneous transplantation into a subject filled with an osmotic delivery device filled with the suspension formulation according to the present invention.

In a further aspect, the invention relates to stimulating insulin secretion, suppressing glucagon secretion, delaying gastric emptying, treating diabetes-related injuries, treating hyperglycemia, treating obesity, regulating appetite, losing weight, and gastrointestinal. Regarding the method of controlling motility.

2.1.0 Formulations and compositions
2.1.1 Particle Preparation In one embodiment, the present invention provides a pharmaceutical composition containing a suspension preparation of an insulin secretagogue peptide such as GLP-1 or exenatide. The suspension composition comprises a non-aqueous single-phase vehicle comprising at least one polymer and at least one solvent. The vehicle preferably exhibits viscous fluid properties. The peptide component contains the insulin secretagogue peptide in the particle preparation dispersed in the vehicle. Typically, the particle formulation comprises a stabilizing component comprising one or more stabilizer components selected from the group consisting of sugars, antioxidants, amino acids, buffers, and inorganic compounds.

Insulin secretagogue peptides useful in the practice of the present invention include, but are not limited to, GLP-1 and exenatide.

Bell, GI et al. (Lund, et al., Proc. Natl. Acad. Sci. USA 79: 345-349 (1982); Patzelt, et al., Nature, 282: 260-266 (1979)) Found to contain three distinct, highly homologous peptide sites called glucagon, glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) (Nature 302). : 716-718 (1983)). Lopez et al. Showed that the peptide sequence of GLP-1 is a sequence of 37 amino acids and that the peptide sequence of GLP-2 is a sequence of 34 amino acids (Proc. Natl. Acad. Sci. USA 80: 5485-5489 (1983)).

A study of the structure of rat preproglucagon revealed a similar pattern of proteolytic cleavage leading to the formation of glucagon, GLP-1, and GLP-2 (Heinrich, G., et al., Endocrinol., 115: 2176-2181 (1984)). The GLP-1 sequences of humans, rats, cattle, and hamsters were found to be identical Ghiglione, M., et al., Diabetologia, 27: 599-600 (1984)).

Cleavage of preproglucagon first produces GLP-1, a 37-amino acid peptide with poor insulin secretagogue activity. Subsequent cleavage of the peptide bond between amino acid residues 6 and 7 produces a biologically active GLP-1, called GLP-1 (7-37) (conventionally). The amino terminus of GLP-1 (7-37) is numbered 7, and the carboxy terminus is numbered 37). Approximately 80% of GLP-1 (7-37) produced by mammals is amidated at the C-terminus after removal of the terminal glycine residue in L-cells, GLP-1 (7-36). Produces amide. The biological effects and metabolic cycles of the free acid GLP-1 (7-37) and the amide GLP-1 (7-36) amide are essentially identical. The sequence of the GLP-1 (7-36) amide is shown in Figure IA.

GLP-1 (including the morphology of the three peptides GLP-1 (1-37), GLP-1 (7-37) and GLP-1 (7-36) amides, as well as analogs of GLP-1) It has been shown to stimulate insulin secretion (ie, insulin secretagogue) that induces cell pumping of glucose and causes a decrease in serum glucose levels (eg, Mojsov, S., Int. J. Peptide Protein). See Research, 40: 333-343 (1992)). Another GLP-1 analog is liraglutide, which is a long-term active DPP-4 resistant GLP-1 receptor agonist. Liraglutide has 97% homology with GLP-1 (7-37). Liraglutide is also referred to as NN-2211 and (Arg34, Lys26)-(N-epsilon- (gamma-Glu (N-alpha-hexadecanoyl))-GLP-1 (7-37) (eg). , U.S. Pat. No. 6,969,702).

Many GLP-1 derivatives and analogs that promote insulin secretion are known in the art (eg, US Pat. Nos. 5,118,666, 5,120,712, 5,512,549, 5,545,618, 5,574,008, No. 5,574,008, No. 5,614,492, No. 5,958,909, No. 6,191,102, No. 6,268,343, No. 6,329,336, No. 6,451,974, No. 6,458,924, No. 6,514,500, No. 6,593,295, No. 6,703,359, No. 6,706,689 No. 6,821,949, No. 6,849,708, No. 6,849,714, No. 6,887,470, No. 6,887,849, No. 6,903,186, No. 7,022,674, No. 7,041,646, No. 7,084,243, No. 7,101,843, No. 7,138,486, No. 7,138,486 See Nos. 7,144,863 and 7,199,217). Therefore, for convenience of consideration herein, the family of GLP-1 derivatives and analogs exhibiting insulin secretagogue action will be collectively referred to as GLP-1.

Gastric inhibitory peptide (GIP) is also an insulinotropic peptide (Efendic, S., et al., Horm Metab Res. 36: 742-6 (2004)). GIP is a hormone secreted by the mucous membranes of the duodenum and jejunum in response to the absorption of fats and sugars that stimulate insulinotropic activity in the pancreas. GIP is also known as glucose-dependent insulinotropic polypeptide. GIP is a 42-amino acid gastrointestinal regulatory peptide that stimulates insulin secretion from pancreatic beta cells in the presence of glucose (Tseng, C, et al., PNAS 90: 1992-1996 (1993)).

Exendin is a peptide isolated from the gila monster venom (Eng, J., et al., J. Biol. Chem., 265: 20259-62 (1990); Eng., J., et al. ., J. Biol. Chem., 267: 7402-05 (1992); US Pat. No. 5,424,286). The exendin has a sequence with certain homology (up to 53% homology to GLP-1 (7-36) amide) with some members of the glucagon-like peptide family (Goke, et al., J. Biol. Chem., 268: 19650-55 (1993)).

Excendin-4 acts on beta-TC1 cells, dispersed acinar cells of the guinea pig pancreas, and GLP-1 cells on the gastric parietal cells of the stomach. The exendin-4 peptide also stimulates somatostatin release and inhibits gastrin release in the isolated stomach (Goke, et al., J. Biol. Chem. 268: 19650-55 (1993); Schepp, et al., Eur. J. Pharmacol., 69: 183-91 (1994); Eissele, et al., Life Sci., 55: 629-34 (1994)). Based on their insulin secretagogue activity, the use of exendin-3 and exendin-4 for the treatment of diabetes and the prevention of hyperglycemia has been proposed (US Pat. No. 5,424,286).

Many derivatives and analogs of exendin-4 that promote insulin secretion are known in the art (eg, US Pat. Nos. 5,424,286, 6,268,343, 6,329,336, 6,506,724, 6,514,500). No. 6,528,486, No. 6,593,295, No. 6,703,359, No. 6,706,689, No. 6,767,887, No. 6,821,949, No. 6,849,714, No. 6,858,576, No. 6,872,700, No. 6,887,470, No. 6,887,849 See Nos. 6,956,026, 6,989,366, 7,022,674, 7,041,646, 7,115,569, 7,138,375, 7,141,547, 7,153,825, 7,157,555). Exenatide is a synthetic peptide that has the same 39 amino acid sequence as exenatide-4. Exenatide is an incretin mimicking peptide that exhibits glycoregulatory activity similar to that of the mammalian incretin hormone glucagon-like peptide 1 (GLP-1). Incretin hormones are hormones that cause an increase in the amount of insulin released when glucose levels are normal, or especially when they are elevated. Incretin hormones affect other activities defined by insulin secretion, such as they reduce glucagon production and delay gastric emptying. In addition, incretin hormones can increase insulin sensitivity and, in some cases, increase islet cell renewal.

For convenience of consideration herein, exenatide-4 peptides, including synthetic versions (eg, exenatide), derivatives and analogs that promote insulin secretion are collectively referred to as eccentric.

In one aspect, the invention provides a particle formulation of an insulin secretagogue peptide that can be used to prepare a suspension formulation. The insulin secretagogue peptide according to the present invention should not be limited by the method of synthesis or production, and is obtained from natural resources or recombinant (produced from either cDNA or genomic DNA), It should include those synthesized or produced by synthesis, gene modification, and gene activation methods. In a preferred embodiment of the invention, the insulin secretagogue peptide is a GLP-1 peptide or exenatide peptide (described above herein), such as GLP-1 (7-36) amide or exenatide. The invention also includes a combination of two or more insulinotropic peptides, such as a combination of GLP-1 (7-36) amide and GIP.

The particle formulation according to the present invention is chemically and physically stable at delivery temperature for at least 1 month, preferably at least 3 months, more preferably at least 6 months, more preferably at least 12 months. The delivery temperature is typically normal human body temperature, eg, about 37%, or slightly higher, eg, about 40%. Further, the particle preparation according to the present invention is stable at a storage temperature of at least 1 month, preferably at least 3 months, preferably at least 6 months, more preferably at least 12 months, preferably chemically and physically. Examples of storage temperatures include, for example, a refrigeration temperature of about 5 ° C, or a room temperature of, for example, about 25 ° C.

About 25% of the peptide particles at delivery temperature after about 3 months, preferably about 6 months, preferably about 12 months, and at storage temperature after about 6 months, about 12 months, and preferably about 24 months. The particle formulation is chemically stable when less than, preferably less than about 20%, more preferably less than about 15%, more preferably less than about 10%, and more preferably less than about 5% form degradation products. Can be considered.

Less than about 10%, preferably about 5% of the peptide particles at the delivery temperature after about 3 months, preferably about 6 months, and at the storage temperature after about 6 months, preferably about 12 months, when the peptide particles are formed. A particle formulation can be considered physically stable when less than, more preferably less than about 3%, more preferably less than about 1% form aggregates.

In order not to lose protein stability, insulin secretagogue peptide solutions are generally stored under frozen conditions and are lyophilized or spray dried and stored in a solid state. Tg (glass transition temperature) can be one factor in considering a stable composition of peptides. Although not intended to be constrained by any particular theory, theories of forming high Tg amorphous solids that stabilize peptides, polypeptides, or proteins have been utilized in the pharmaceutical industry. In general, when an amorphous solid has a high Tg such as 100 ° C, the peptide product cannot have fluidity even when stored at room temperature or 40 ° C. This is because the storage temperature is below Tg. Calculations using molecular information show that when the glass transition temperature is above, the fluidity of the molecule is 0 even at a storage temperature of 50 ° C. The lack of fluidity of a molecule corresponds to not having the problem of instability. Tg also depends on the water content level in the product formulation. In general, the higher the water content, the lower the Tg of the composition.

Therefore, in some aspects of the invention, high Tg excipients such as sucrose (Tg = 75 ° C.) and trehalose (Tg = 110 ° C.) are included in the protein formulation to improve stability. Is done. Preferably, the particle formulation is spray-dried, lyophilization, desiccation, freeze-drying, flouring, granulation, ultrasonic drop creation, crystallization, precipitation, etc. Alternatively, it may be formed into particles using a process such as another technique available in the art to form particles from a mixture of multiple components. The particles are preferably substantially uniform in shape and size.

A typical spray drying process involves filling a spray solution containing a peptide such as, for example, an insulin secretagogue peptide (eg GLP-1 (7-36) amide or exenatide), and stabilizing excipients in the sample chamber. Can include. The sample chamber is typically maintained at the desired temperature, eg freezing to room temperature. Freezing generally promotes protein stability. The solution, emulsion, or suspension is introduced into a spray dryer that atomizes the fluid into droplets. Droplets can be formed by the use of rotary atomizers, pressure nozzles, pneumatic nozzles, or sonic nozzles. The mist of droplets comes into immediate contact with the drying gas in the drying chamber. The dry gas removes the solvent from the droplets and carries the particles to the recovery chamber. In spray drying, the factors that affect yield are, but are not limited to, charge localization on the particles (which can facilitate the binding of the particles to the spray dryer) and the aerodynamics of the particles (which can make particle recovery difficult). including. In general, the yield of the spray drying process depends in part on the particle formulation.

In one aspect of the invention, the particles are sized so that they can be delivered via a drug delivery device. The uniform shape and size of the particles typically helps to provide a consistent and uniform rate of release from the delivery device or the like. However, particle preparations with a non-uniform particle size distribution can also be used. For example, in a typical implantable osmotic delivery device with a delivery opening, the particle size is less than about 30%, preferably less than 20%, more preferably less than 10% of the diameter of the delivery opening. be. In one embodiment of the particle formulation used in an osmotic delivery system where the delivery of the implant has a diameter in the range of, for example, about 0.1 to 0.5 mm, the particle size is preferably less than about 50 microns, more preferably about. It can be less than 10 microns, more preferably in the range of about 3 to about 7 microns. In one embodiment, the opening is about 0.25 mm (250 μm) and the particle size is about 3-5 μm.

In a preferred embodiment, when the particles are encapsulated in a suspension vehicle, their settle period is no less than about 3 months at delivery temperature. It is generally said that small particles tend to have a lower settling rate in a viscous suspension vehicle than large particles. Therefore, micro to nano size particles are typically desirable. In one embodiment of the particle formulation according to the invention used in implantable osmotic delivery systems where the delivery of the implant has a diameter ranging from, for example, about 0.1 to 0.5 mm, the particle size is preferably about 50. It can be in the range of less than micron, more preferably less than about 10 microns, more preferably about 3 to about 7 microns.

In one embodiment, the particle formulation according to the present invention comprises one or more insulin secretagogue peptides as described above, one or more stabilizers, and optionally a buffer. The stabilizer can be, for example, a sugar, an antioxidant, an amino acid, a buffer, or an inorganic compound. The amount of the stabilizer and the buffer in the particle formulation can be determined experimentally based on the activity of the stabilizer and the buffer and the desired properties of the formulation. Typically, the amount of sugar in the formulation is determined in relation to agglutination. In general, sugar levels should not be too high to avoid promoting crystal growth in the presence of water due to excess sugar that is not bound to the insulin secretagogue peptide. Typically, the amount of antioxidant in the formulation is determined in relation to oxidation, while the amount of amino acids in the formulation is in relation to oxidation and / or in the process of spray drying. It is determined in relation to the particle forming ability. Typically, the amount of buffering agent in said formulation is determined in relation to pre-processing, stability, and particle forming ability in the process of spray drying. NS. A buffer may be needed to stabilize the insulin secretagogue peptide when all excipients are solubilized, for example during treatment processes such as solution preparation and spray drying.

Examples of sugars that can be contained in the particle preparation include, but are not limited to, monosaccharides (eg, fructose, maltose, galactose, glucose, D-mannose, and sorbose), disaccharides (eg, lactose, sucrose, trehalose). , And cellobiose), polysaccharides (eg, raffinose, meregitos, maltodextrin, dextran, and starch), and algitol (chain polyols; eg, mannose, xylitol, multiol, lactitol, xylitol, sorbitol, pyranosyl, sorbitol, and myo). Insitol) is included. Preferred sugars are non-reducing sugars such as sucrose, trehalose, and raffinose.

Examples of antioxidants that may be included in the particle formulation are, but are not limited to, methionine, ascorbic acid, sodium thiosulfate, catalase, platinum, ethylenediamine tetraacetic acid (EDTA), citric acid, cysteine, thioglycerol, thioglycolic acid. , Thiosorbitol, butylated hydroxyanisole, butylated hydroxytoluene, and propyl gallate.

Examples of amino acids that can be contained in the particle preparation include, but are not limited to, arginine, methionine, glycine, histidine, alanine, L-leucine, glutamic acid, isoleucine, L-threonine, 2-phenylalanine, valine, norvaline, praline, Includes phenylalanine, tryptophan, serine, asparagine, cysteine, tyrosine, lysine, and norleucine. Preferred amino acids include those that are easily oxidized, such as cysteine, methionine, and tryptophan.

Examples of buffers contained in the particle formulation include, but are not limited to, citrate, histidine, succinate, phosphate, maleate, tris, acetate, sugar, and gly-gly. Is done. Preferred buffers include citrate, histidine, succinate, and tris.

Examples of inorganic compounds contained in the particle formulation include, but are not limited to, NaCl, Na ₂ SO4, י ₃ , KCl, KH ₂ PO4, CaCl ₂ , and MgCl ₂ .

In addition, the particle formulation may contain other excipients such as surfactants, fillers, and salts. Examples of surfactants include, but are not limited to, polysorbate 20, polysorbate 80, PLURONIC® (BASF Corporation, Mount Olive, NJ) F68, and sodium dodecyl sulfate (SDS). Examples of fillers include, but are not limited to, mannitol and glycine. Examples of salts include, but are not limited to, sodium chloride, calcium chloride, and magnesium chloride.

Typically, all compounds contained in the particle formulation are acceptable for pharmaceutical use in mammals, especially humans.

Table 1 below shows an example of the particle formulation component range in particles containing exenatide.

In one embodiment, the exenatide particle preparation comprises an exenatide peptide, sucrose (sugar), methionine (antioxidant) and sodium citrate / citric acid (citric acid buffer).

Table 2 below shows an example of the particle formulation component range for particles containing GLP-1.

Within these weight percent of the components of the particle formulation, some preferred component ratios are: insulin-promoting peptides (eg, exenatide or GLP-1) and antioxidants (eg, methionine) -1/10. , 1/5, 1 / 2.5, 1/1, 2.5 / 1, 5/1, 10/1, preferably about 1/3 to 3/1 (same component ratios are insulin secretagogue peptides and amino acids ); Insulin-promoting peptides (eg, exenatide or GLP-1) and sugars (eg, sucrose) -1/20, 1/10, 1/5, 1/2, 5/1, 10/1, 20/1, preferably about 1/5 to 5/1, more preferably about 1/3 to 3/1; and / or with an insulin secretagogue peptide (eg, exenatide or GLP-1). Antioxidant + sugar (eg methionine + insulin) -1/20, 1/10, 1/5, 1/2, 5/1, 10/1, 20/1, preferably about 1/5 to 5 / 1, more preferably about 1/3 to 3/1 (the same component ratio applies to the ratio of insulin secretagogue peptide to amino acid + sugar). The present invention also relates to, for example, about 1/20 to about 20/1, about 1/10 to about 10/1, about 1/5 to about 5/1, and others, for example, about 1/5 to about 3/1. Etc., Includes ranges corresponding to all these ratios.

Taken together, the insulin-promoting peptide is formulated in a solid state in a dry powder, thereby preserving the highest chemical and biological stability in the protein or peptide. The particle formulation exhibits long-term storage stability at high temperatures, and thus makes it possible to deliver a stable and biologically effective peptide to a subject over a long period of time.

The particle size distribution of the dried particle powder can be well adjusted (0.1 micron to 20 micron) by preparing the preparation using, for example, a spray drying method or a freeze drying method. The processing parameters for the preparation of the dry powder are optimized to produce particles with the desired particle size distribution, density and surface area.

The selected excipients and buffers in the particle formulation, for example: modify the density of the pre-dried powder; the physical stability of the peptide (eg, high glass transition temperature, and avoidance of phase transition). Maintain; use of filler results in uniform dispersion in suspension; change in hydrophobicity and / or hydrophilicity to process the solubility of the dry powder in the selected solvent; and in the product. It may provide the ability to adjust the pH (for solubility and stability) while adjusting and maintaining the pH.

The particle preparation according to the present invention is exemplified herein with respect to exenatide and GLP-1 (7-36) amide as typical insulin secretagogue peptides (see Examples 1 and 2). ). These examples are not intended to be limiting.

2.1.2 Vehicle and Suspension Formula In one aspect of the present invention, the suspension vehicle provides a stable environment in which the insulin secretagogue peptide particle formulation is dispersed. The particle formulation is chemically and physically stable (same as above) in the suspension vehicle. Suspended vehicles typically include one or more polymers and one or more vehicles that form a solution that is viscous enough to uniformly suspend the particles containing the insulin secretagogue peptide.

The viscosity of the suspended vehicle is typically sufficient to prevent the particle formulation from precipitating during storage and to be used in delivery methods such as, for example, implantable drug delivery devices. The suspended vehicle is biodegradable in that it disintegrates or decomposes over a period of time corresponding to the biological environment. Disintegration of the suspended vehicle is one or more physical, such as enzymatic activity, oxidation, reduction, hydrolysis (eg, proteolysis), substitution (eg, ion exchange), or solubilization by solubilization, emulsion or micelle formation. Or it can be caused by a chemical decomposition process. After disintegration of the suspended vehicle, the components of the suspended vehicle are absorbed and otherwise dispersed by the patient's body and surrounding tissues.

The solvent in which the polymer is dissolved can affect the properties of the suspension product, such as the behavior of the insulin secretagogue peptide particle preparation during storage. The solvent is selected in combination with the polymer such that the resulting suspended vehicle exhibits phase separation upon contact with the aqueous environment. In some embodiments of the invention, the solvent is selected in combination with a polymer such that the resulting suspended vehicle exhibits phase separation upon contact with an aqueous environment containing at least about 10% water. ..

The solvent can be an acceptable solvent that is immiscible with water. Also, the solvent may be selected such that the polymer dissolves in the solvent at a high concentration, such as a polymer concentration greater than about 30%. However, typically, the insulin secretagogue peptide is substantially insoluble in the solvent. Examples of solvents useful for practicing the present invention are, but are not limited to, lauryl alcohol, benzyl benzoate, benzyl alcohol, lauryl lactate, decanol (also referred to as decyl alcohol), ethylhexyl lactate, and long chains (C ₈ ~. C ₂₄ ) Contains fatty alcohols, esters, or mixtures thereof. The solvent used in the suspension vehicle can be "dry" in that it has a low water content. Preferred solvents for use in the formulation of the suspended vehicle include lauryl lactate, lauryl alcohol, benzyl benzoate, and combinations thereof.

Examples of polymers for the formulation of suspended vehicles according to the present invention are, but are not limited to, polyesters (eg, polylactic polyglycolic acid or polylactic polyglycolic acid), pyrrolidones (eg, about 2,000 to about 1,000,000). Includes polyvinylpyrrolidone (PVP) with a range of molecular weights, polyoxyethylene polyoxypropylene block copolymers, or mixtures thereof. In one embodiment, the polymer is a PVP with a molecular weight of 2,000 to 1,000,000. In a preferred embodiment, the polymer is polyvinylpyrrolidone K-17 (typically having an average molecular weight of about 7,900 to 10,800). Polyvinylpyrrolidone can be characterized by a K-value, which is an indicator of viscosity (eg K-17). The polymers used in the suspension vehicle may include one or more different polymers, or may include a single polymer of different grades. In addition, the polymer used in the suspension vehicle may be dry or have a low water content.

Generally speaking, the suspension vehicle according to the present invention may vary in composition based on the desired performance characteristics. In one response, the suspended vehicle is about 40% to about 80% (w / w) of polymer (s) and about 20% to about 60% (w / w) of solvent (s). May include. Preferred embodiments of the suspension vehicle include: solvent: about 25%, and polymer: about 75%; solvent: about 50%, and polymer: about 50%; solvent: about 75%, and polymer: about 25%. Includes a vehicle composed of a polymer (s) and solvent (s) combined in proportion.

The suspended vehicle may exhibit Newtonian behavior. The suspended vehicle is typically formulated to provide a viscosity that maintains a uniform dispersion of the particle formulation over a predetermined period of time. This aids in facilitating the production of suspension formulations tailored to provide regulated delivery of the insulin secretagogue peptide at the desired rate. The viscosity of the suspended vehicle can vary depending on the desired application, the size and type of the particle formulation, and the filling of the suspended vehicle with the particle formulation. The viscosity of the suspended vehicle can be varied by varying the type or relative amount of solvent or polymer used.

The suspended vehicle may have viscosities ranging from about 100 poises to about 1,000,000 poises, preferably from about 1000 poises to about 100,000 poises. The viscosity can be measured using a parallel plate rheometer at a shear rate of ^10-4 / sec at 37 ° C. In some embodiments, the viscosity of the suspended vehicle can range from about 5,000 poise to about 50,000 poise. In some preferred embodiments, the viscosity range can be between about 12,000 and about 18,000 poises at 33 ° C.

The suspended vehicle may exhibit phase separation when in contact with an aqueous environment; typically, the suspended vehicle exhibits substantially no phase separation depending on the temperature. For example, in the temperature range from about 0 ° C to about 70 ° C, and in temperature cycles such as the 4 ° C-37 ° C-4 ° C cycle, the suspended vehicle typically does not exhibit phase separation.

The suspended vehicle can be prepared by combining a polymer and a solvent under dry conditions such as in a drying box. The polymers and solvents can be combined at high temperatures such as about 40 ° C to about 70 ° C to allow liquefaction and formation of a single phase. The materials can be mixed in vacuum to remove air bubbles resulting from them. The materials can be combined by using a normal mixer such as a double helix blade or a similar mixer at a speed of about 40 rpm. However, higher speeds can also be used to mix those materials. When the liquid solution formation of the material is achieved, the suspended vehicle is cooled to room temperature. Differential scanning calorimetry (DSC) can be used to verify that the suspended vehicle is a single phase. In addition, the components of the vehicle (eg, the solvent and / or the polymer) can be treated to substantially reduce or substantially remove peroxides (eg, treatment with methionine; eg, US Patent Publication). See Gazette No. 2007-0027105).

The particle preparation containing the insulin secretagogue peptide is added to the suspension vehicle to form the suspension preparation. The suspension product can be prepared by dispersing the particle product in the suspension vehicle. The suspended vehicle can be heated and the particle formulation is added into the suspended vehicle under dry conditions. The materials can be mixed in vacuum at high temperatures such as about 40 ° C to 70 ° C. The materials may be mixed in the suspended vehicle at a sufficient rate, such as about 40 rpm to about 120 rpm, and for a sufficient time, such as about 15 minutes, in order for the particle formulation to achieve uniform dispersion. The mixer can be a double helix blade or other suitable mixer. The resulting mixture is removed from the mixer and sealed during the drying phase to prevent contamination of the suspended pharmaceutical product with moisture and, for example, a implantable drug delivery device, a unit dose container. Alternatively, cool to room temperature prior to further use, such as filling in a multiple-dose container.

The suspended vehicle typically has an overall moisture content of less than about 10 wt%, preferably less than about 5 wt%, and more preferably less than about 4 wt%.

The suspension formulations according to the invention are exemplified below herein with respect to exenatide and GLP-1 (7-36) amide as typical insulin secretagogue peptides. These illustrations are not intended to be limiting.

In summary, the components of the suspended vehicle provide biocompatibility. The components of the suspension vehicle provide physicochemical properties suitable for the formation of stable suspensions, such as dry powder particle formulations. These properties include, but are not limited to: viscosity of suspension; purity of vehicle; residual moisture of vehicle; density of vehicle; compatibility with dry powder; compatibility with transplanting equipment; molecular weight of polymer; vehicle Stability; as well as the hydrophobicity and hydrophilicity of the vehicle. These properties can be manipulated and adjusted, for example, by altering the vehicle composition and by manipulating the proportions of the components used in the suspended vehicle.

3.0.0 Delivery of Suspension Formulas The suspension formulations described herein are portable to provide sustained delivery of the compound over a long period of weeks, months, or even approximately one year. Can be used in various drug delivery devices. Such implantable drug delivery devices typically allow delivery of the compound at a desired flow rate over a desired period of time. The suspension product is filled in the implantable drug delivery device by a conventional technique.

The suspension product can be delivered, for example, by osmotic pressure using a drug delivery device or the like that is mechanically, electromechanically, or chemically driven. The insulin secretagogue peptide is delivered at a therapeutically effective flow rate to a subject requiring treatment with the insulin secretagogue peptide.

The insulin secretagogue peptide can be delivered over a period ranging from about 1 week to about 1 year or longer, preferably from about 1 month to about 1 year or longer, more preferably from about 3 months to about 1 year or longer. The implantable drug delivery device may include a container having at least one opening through which the insulin secretagogue peptide is delivered. The suspension product is stored in the container. In one embodiment, the implantable drug delivery device is an osmotic delivery device, the delivery of the drug is driven by osmotic pressure. Some osmotic delivery devices and their components are described, for example, in DUROS® delivery devices or similar devices (eg, US Pat. Nos. 5,609,885, 5,728,396, 5,985,305, etc.). 5,997,527, 6,1 13,938, 6,132,420, 6,156,331, 6,217,906, 6,261,584, 6,270,787, 6,287,295, 6,375,978, 6,395,292, 6,508,808, 6,544,252 , 6,635,268, 6,682,522, 6,923,800, 6,939,556, 6,976,981, 6,997,922, 7,014,636, 7,207,982, 7,112,335, 7,163,688, US Patent Publication No. 2005-0175701 , 2007-0281024, and 2008-0091176).

The DUROS® delivery device typically consists of a cylindrical container containing an osmotic engine, a piston, and a drug formulation. The container is sealed at one end with a controlled-rate water-permeable membrane and at the other end with a diffusion moderator, and the drug product is sealed from the drug container. It is released through it. The piston isolates the formulation from the osmotic engine and utilizes a sealant to prevent water from entering the osmotic engine compartment from the drug container. The diffusion control membrane, together with the drug preparation, is designed to prevent body fluids from entering the drug container through the opening.

The DUROS® device releases the therapeutic agent at a predetermined rate based on the principle of osmotic pressure. Extracellular fluid is delivered through a semipermeable membrane into a DUROS® device, directly into a salt engine that expands the piston to drive it at slow and moderate delivery rates. Infiltrate. The movement of the piston causes the drug product to be released through an opening or exit port at a predetermined sheer rate. In one embodiment of the present invention, the container of the DUROS® apparatus is filled with the suspension formulation according to the present invention containing, for example, GLP-1 (7-36) amide or exenatide, and the apparatus is the device thereof. It is possible to deliver the suspension product to the subject over a long period of time (eg, about 3, about 6, or about 12 months) at a predetermined, therapeutically effective delivery rate.

Transplantable devices, such as the DUROS® device, are used in the administration of beneficial drug agents to:: Pharmacokinetic true zero-order release of the beneficial drug; long-term release ( For example, over about 12 months); and provides the advantages of stable delivery and dosing of beneficial agents.

Provides constant spills, controlled spills, or programmable spills available from Codman & Shurtleff, Inc. (Raynham, MA), Medtronic, Inc. (Minneapolis, MN), and Tricumed Medinzintechnik GmbH (Germany), usually Other implantable drug delivery devices, which may include implantable pumps of the same type, can be used in the practice of the present invention.

A implantable device, such as the DUROS® device, upon administration of the suspension formulation according to the invention: the pharmacokinetic true zero-order release of the insulin secretagogue peptide; It provides the advantages of long-term release (eg, over about 12 months); and stable delivery and dosing of insulin secretagogue peptides.

The amount of beneficial agent employed in the delivery apparatus according to the invention means the amount required to deliver the amount of therapeutically effective agent to achieve the desired therapeutic result. In fact, this can vary depending on, for example, differences in specific agents, delivery sites, disease progression, desired therapeutic effects, and the like. Typically, in an osmotic delivery device, the volume of the beneficial drug chamber containing the beneficial drug formulation is between about 100 μl and about 1000 μl, more preferably between about 120 μl and about 500 μl, more preferably about 150 μl and up. It is between about 200 μl.

Typically, the osmotic delivery device is implanted within the subject, eg, subcutaneously. The device (s) may be inserted into one or both arms (eg, medial, lateral or dorsal of the upper arm), or abdomen. A preferred location in the abdomen is under the abdominal skin in the area that extends between the bottom of the ribs and above the beltline. To provide multiple sites for inserting one or more osmotic delivery devices into the abdomen, the peritoneum is below: 5-8 cm below the right rib and 5-8 cm right from the center line. Upper right part, 5-8 cm above the belt line, 5-8 cm to the right of the center line, lower right part, 5-8 cm below the left rib, about 5-8 cm from the center line It is divided into quarters like the upper left part to the left and the lower left part 5 to 8 cm above the belt line and 5 to 8 cm to the left from the center line. This provides multiple available sites for implanting one or more devices in one or more situations.

The suspension may also be delivered from a non-transplantable or non-transplanted drug delivery device, such as an external pump such as a perista pump used for subcutaneous delivery in a hospital.

The suspension formulation according to the present invention is also used in an infusion pump such as an ALZET® (DURECT Corporation, Cupertino CA) osmotic pump, which is a small infusion pump for continuous dosing of experimental animals. obtain.

The suspension according to the present invention can also be used in the form of injection to provide a high concentration bolus dose of the biologically active insulin secretagogue peptide.

In one embodiment of the invention, for example, derivatives and analogs of GLP-1 having a short half-life after injection into the human body from a implantable device (eg, GLP-1 (7-36) amide or exenatide). Sustained delivery of is particularly beneficial. In addition, by using a implantable device such as the DUROS® device for delivery of insulin secretagogue peptides, it is possible to reduce the side effects associated with infusion and the convenience of administration. Improves treatment compliance while improving. The duration of drug delivery from a single transplant can be weeks or even a year.

Some advantages and benefits of the suspension formulations according to the invention delivered via an osmotic delivery device such as a DUROS® device include, but are not limited to: Improved treatment compliance results in improved efficacy, and such improved compliance can be achieved using an osmotic delivery device that is implanted. Implantable osmotic devices, such as the DUROS® device, provide a continuous and constitutive 24 hour drug (eg, GLP-1 or exenatide) 24 hours a day for better blood glucose levels than throughout the day. It may be adjusted and the effectiveness of the treatment may be improved. In addition, incretins and incretin mimetics can protect beta cells in the pancreas and slow the progression of type 2 diabetes. Thus, 24-hour sustained and constitutive drug delivery of incretins or incretin mimetics by said DUROS® apparatus still provides significant protection of beta cells and may also result in improved disease progression. .. Also, since the sustained delivery of the insulin secretagogue peptide (eg, GLP-1 or exenatide) from the DUROS® device allows the treated subject full flexibility in dietary planning. It improves the quality of life compared to, for example, the time-consuming treatment of bolus injections associated with the main meal of the day. Also, unlike other sustained release preparations and depot injections, drug administration when using a DUROS® device removes the device, for example, when safety issues arise in a particular subject. This can be stopped immediately.

In addition to GLP-1 derivatives and analogs that promote insulin secretion, other GLP-1 derivatives (eg (GLP-1 (9-36) amide) reduce blood glucose by a mechanism that does not contain insulin secretion. It has been shown to cause (Deacon, CF, et al., Am. J. Physiol. Endocrinol. Metab. 282: E873-E879 (2002)). In addition, GLP-1 (9-36) amides are used in the stomach. It has been shown to reduce postprandial blood glucose independently of content excretion and insulin secretion (Meier, JJ, et al., Am. J. Physiol. Endocrinol. Metab. 290: E1118-E1123 (2006)). Therefore, in another aspect, the invention is essentially the same as for GLP-1 derivatives and analogs that exhibit the insulin secretagogue action as described above, of such GLP-1 derivatives. Includes delivery of these suspensions to the subject, particle formulations, suspensions of those particles in the vehicle, and subjects for reducing insulin and / or postprandial blood glucose, in addition to GIP (3-. 42) is considered to be a weak GIP receptor antagonist that does not act on insulin-related glucose regulation. Such GIP derivatives can also be formulated in the guidance described herein (alone or otherwise). In combination with peptides).

The present invention also includes a method for producing a preparation according to the present invention, which comprises the particle preparation, the suspension vehicle, and the suspension preparation described above in the present specification.

4.0.0 Use of Suspension The Suspensions described herein provide a promising alternative to insulin therapy in diabetic subjects. Diabetes type 2 or type 2 diabetes (non-insulin dependent diabetes mellitus (NIDDM)) is a metabolic disorder primitively characterized by insulin resistance, relative insulin deficiency, and hyperglycemia. The suspension preparation according to the present invention containing an insulin secretagogue peptide is useful for stimulating insulin secretion, suppressing glucagon secretion, delaying gastric emptying, and in some cases increasing insulin sensitivity in peripheral tissues such as muscle and fat. Is.

The suspension preparation according to the present invention includes diabetic diseases (eg, diabetes mellitus and gestational diabetes) and diabetes-related diseases (eg, diabetic myocardium, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retina). Diabetes mellitus, hyperglycemia, hyperglycemia, hyperglycemia, hyperinsulinemia, hyperlipidemia, atherosclerosis, and tissue ischemia, which is especially myocardial ischemia), or hyperglycemia (eg, beta blockers, Reduced feeding (eg, associated with treatment with drugs that increase the risk of hyperglycemia), including thiazide diabetic drugs, corticosteroids, niacin, pentamidin protease inhibitors, L-asparaginase, and some antipsychotics. It may be useful in the treatment of obesity treatment, appetite regulation, or weight loss), stroke, reduction of plasma lipids, acute coronary syndrome, hibernating myocardium, control of gastrointestinal motility, and increased urinary flow.

In addition, the suspension formulations according to the invention can be potential appetite regulators in the subject treated with those formulations.

In one embodiment, the suspension formulation is administered using an osmotic delivery device as described above. Examples of target rates for delivery of suspension formulations according to the invention comprising insulin secretagogue peptides are not limited: particle formulations containing GLP-1 (eg, GLP-1 (7-36) amide). For suspension formulations containing, for example, between about 20 μg / day and about 900 μg / day, preferably between about 100 μg / day and about 600 μg / day, for example about 480 μg / day; and suspensions containing particle formulations containing exenatide. In the case of a pharmaceutical product, it comprises between about 5 μg / day and about 320 μg / day, preferably between about 5 μg / day and about 160 μg / day, for example, about 10 μg / day to about 20 μg / day. The exit sheer rate of the suspended product from the osmotic delivery device is the target delivery rate of the insulin secretagogue peptide to the target, and the sustained release of the suspended product from the osmotic delivery device. And it is determined to be reasonably achieved by uniform delivery. Examples of emission permeation rates are, but are not limited to, about 1 to about 1 x 10 ^-7 reciprocal seconds, preferably about 4 x 10 ^-2 about 6 x 10 ^-4 reciprocal seconds, more preferably about 5 x 10 ^-3 about. Includes 1 × 10 ^-3 reciprocal seconds.

Subjects treated with the suspension formulations according to the invention include other agents (eg, sulfonylurea, meglitinide (eg, repaglinide, and nateglinide), metformin, and combinations of such agents), alpha glucosidase inhibitors, amylin (eg, sulfonylurea, and a combination of such agents). Alternatively, it may also benefit from treatment with synthetic analogs such as pramlintide), dipeptidyl peptidase IV (DPP-IV) inhibitors (eg sitagliptin and vildagliptin), and long-acting / fast-acting insulin.

Oral use of an oral dipeptidyl peptidase-IV (DPP-IV or DPP-4) inhibitor to prevent cleavage of GLP-1 causes the suspension product according to the present invention to cleave with dipeptidyl peptidase-IV. It is significantly useful when containing GLP-1 variants (see, eg, US Pat. No. 7,205,409).

Example 5 represents data showing that delivery of a pharmaceutical product containing exenatide using a DUROS® device caused a decrease in glucose levels and a decrease in body weight.

Other objectives may be clarified by those skilled in the art by reviewing the following specification and claims.

Experiments The following examples are presented to those of skill in the art to provide a complete disclosure and description of the devices, methods, and methods of manufacturing and using the formulations according to the invention, invented by the inventor. It is not intended to limit the scope of what is considered to be. We strive to be accurate with respect to the numbers used (eg quantity, temperature, etc.), but may include some experimental error and deviation. Unless suggested, parts are parts by weight, molecular weight is average molecular weight, temperature is Celsius degrees, and pressure is at or near atmospheric pressure.

The composition produced by the present invention conforms to the specifications of composition and purity required to be a pharmaceutical product.

Example 1
Exenatide Particle Preparation This example describes the preparation of an exenatide particle preparation.

A. Formula 1
Exenatide (0.25 g) was dissolved in 50 mM sodium citrate buffer at pH 6.04. The solution was dialyzed against a pharmaceutical solution containing sodium citrate, sucrose, and methionine. And the pharmaceutical solution uses Buchi290, which has a 0.7 mm nozzle, an outlet temperature of 75 ° C., a vaporization pressure of 100 Psi, a solid content of 2%, and a flow rate of 2.8 mL / min. And spray dried. The dry powder contained 21.5% exenatide and 4.7% residual water and had a density of 0.228 g / ml.

B. Formulas 2 and 3
Two additional exenatide formulations were prepared essentially by the method described above. In Table 3 below, the weight percent (wt%) of the constituents of the above-mentioned preparations 1, 2 and 3 are summarized.

Example 2
GLP-1 Dry Powder This example describes the preparation of a GLP-1 (7-36) amide particle formulation.
GLP-1 (7-36) amide (1.5 g) was dissolved in 5 mM sodium citrate buffer at pH 4. The solution was dialyzed against a pharmaceutical solution containing sodium citrate buffer and methionine. And the pharmaceutical solution is equipped with a 0.7 mm nozzle, using Buchi290 with an outlet temperature of 70 ° C., a vaporization pressure of 100 Psi, a solid content of 1.5% and a flow rate of 5 mL / min. It was spray dried. The dry powder contained 90% GLP-1 (7-36) amide.

Example 3
Exenatide Suspension Formula This example describes the preparation of a suspension formulation comprising a suspension vehicle and an exenatide particle formulation.

A. Suspension formulation of 20 wt% exenatide particles The exenatide particle formulation was prepared by spray drying and contained 20 wt% exenatide, 32 wt% sucrose, 16 wt% methionine, and 32 wt% citrate buffer.

The suspended vehicle was formed by dissolving the polyvinylpyrrolidone polymer in a benzyl benzoate solvent in a weight ratio of about 50/50. The viscosity of the vehicle was about 12,000 to 18,000 poises when measured at 33 ° C. Particles containing the peptide exenatide were dispersed throughout the vehicle at a concentration of 10 wt%.

B. Suspended Formulas of Particle Formulations 1, 2 and 3 Suspended vehicles have a polyvinylpyrrolidone K-17 (typically with an average molecular weight in the range of about 7,900 to 10,800) in dry air and under reduced pressure. The polymer was formed by dissolving the polymer in a benzyl benzoate solvent heated to about 65 ° C. in a weight ratio of about 50/50. The viscosity of the vehicle was about 12,000 to 18,000 poises when measured at 33 ° C. The particle formulations 1 to 3 described in Example 1 were dispersed throughout the vehicle at the concentrations (weight percent) shown in Table 4.

Example 4
GLP-1 (7-36) Amide Formula This example describes the preparation of a suspension formulation comprising a suspension vehicle and a GLP-1 (7-36) amide particle formulation. The GLP-1 (7-36) amide particle formulation was prepared by spray drying and contained 90 wt% GLP-1, 5 wt% methionine, and 5 wt% citrate buffer.

The suspended vehicle containing the polyvinylpyrrolidone polymer was dissolved in a benzyl benzoate solvent in a weight ratio of about 50/50. The viscosity of the vehicle was about 12,000 to 18,000 poises when measured at 33 ° C. Particles containing the peptide GLP-1 (7-36) amide were dispersed throughout the vehicle at a concentration of 33% by weight.

Example 5
Treatment with continuous delivery of exenatide using the DUROS® device Decreased glucose levels and weight loss in animals The data in this example are the sustained and constitutive delivery of exenatide formulations from the DUROS® device. The effect on glucose level and body weight in the Zucker Diabetic Fatty (ZDF) rat model of type 2 diabetes was shown.

The ZDF rat model has previously been described as an accurate model of type 2 diabetes based on aberrant glucose resistance caused by a genetic obesity gene mutation that results in insulin resistance (eg, Clark, J., et al.,, Proc. Soc. Exp. Biol. Med. 173: 68-75 (1983); Peterson, RG, et al., ILAR News 32: 16-19 (1990); Peterson, RG, In Frontiers in Diabetes Research. Lessons from Animal Diabetes III, edited by E. Shafrir, pp. 456-458. London: Smith-Gordon (1990); Vrabec, JT, Otolaryngol. Head Neck Surg 118: 304-308 (1998); Sparks, JD, et al. , Metabolism 47: 1315-1324 (1998), etc.).

The study designs shown in Table 5 were used.

Rats in the treatment group (group 2 (obesity) and group 3 (slimming), n = 6 / group) had 7 cycles in 24 hours, DUROS® device (where the device was on day 1). Rats (suspended formulation 2: Example 3, Table 4) in the control group, while exposed to 20 mcg / day exenatide (suspended formulation 2: Example 3, Table 4) delivered continuously using (inserted and removed on day 8). A fake drug device was inserted in group 1; n = 6). The DUROS® device was inserted subcutaneously into each animal.

The following endpoints were evaluated during the processing period. Clinical signs / mortality were assessed at least once daily. Body weight was determined before transplantation, daily during the observation period, and at the end. Blood glucose was determined as follows: fasting blood samples were collected on days 1 and 8; and 3 times daily (at intervals of 4-6 hours) (but day 1). And twice on the 8th day) Non-fasting blood samples were taken. Blood glucose was determined using the OneTouch Ultra® (Johnson & Johnson, New Brunswick N.J.) Blood Glucose Measuring Instrument. Glucose levels were measured 3 times daily. Quantitative HbA1c was determined using the DCA 2000 Plus Analyzer (GMI, Inc., Ramsey Minn.) In fasting blood samples collected on days 1 and 8. Continuous blood samples were obtained before (0), 12, 24, 36, 48, 72 hours, and 5 and 7 days after transplantation. These samples were centrifuged, plasma was collected, and stored at -70 ° C. Microscopic examination, including autopsy, was performed on the 8th day of the observation period.

FIG. 2 represents the data obtained for the average body weight (grams) of the group. Weight loss was observed by day 4 in both exenatide-treated obesity (Figure 2: black squares) and slimming (Figure 2: black triangles) rats (obesity: day 1 = 4th day = 296.2 ± 14.2g (p <0.01) for 329 ± 15.2g; and slimming: 1st day = 265.4 ± 9.1g vs. 4th day = 237.6 ± 7.8g (p <0.01)). Overall, by day 6, treated obese rats lost 10.7% and treated lean rats lost 15.1%. In contrast, obese rats treated with a placebo device (Figure 2: black diamonds) gained a slight weight (1.8%) by day 6.

FIG. 3 shows the data obtained at the mean blood glucose concentration (mg / dL) of the group. Within 1 day after insertion of the DUROS® device, reduced blood glucose levels in treated obese rats (Figure 3; black-painted squares) compared to obesity controls (Figure 3; black-painted diamonds). Is clear. Mean glucose levels in the first treated obese rats on day 3 were 163 ± 92 mg / dL, compared with 481 ± 47 mg / dL in obese control rats (p <0.05). Between 3 and 7 days, blood glucose levels in obese rats treated with 20 mcg / day exenatide decreased near the values in slimming animals, but glucose in obese rats treated with placebo. The average level was 502 mg / dL. Glucose levels in slimming animals (Figure 3: black triangles) were always around 100 mg / dL. A glucose level of 100 mg / dL is considered normal.

FIG. 4 shows the data obtained in the mean blood HbA1c value of the group. Over the study period, treated obese rats (Figure 4; black squares) showed an overall increase in HbA1c levels of 5.8%, whereas obese control rats (Figure 4; black diamonds) showed a 6.7% increase. showed that. In some treated obese rats, mean blood glucose levels were reduced during the period, but no corresponding reduction in HbA1c was observed in these animals. This result may be due to the fact that the period of the study was not long enough, whereas the HbA1c level required a period of 1 to 2 months or more to be proportional to the average blood glucose concentration. ..

These data indicate that sustained and uniform delivery of exenatide results in a glucose lowering in treated animals with a strong effect on body weight. These results support the use of the DUROS® device in the treatment of human diabetes to administer incretin mimetics, such as suspension formulations containing exenatide, in a steady state for extended periods of time.

As will be apparent to those skilled in the art, various modifications and variations of the above embodiments may be made without departing from the spirit and scope of the invention. Such changes and changes are within the scope of the invention.

Claims (17)

It is a suspension product, and the following:
A particle formulation containing an insulin-promoting peptide, antioxidant, sugar and buffer, wherein the insulin-promoting peptide is at least one of exenatide, a derivative of exenatide and an analog of exenatide; and about. A non-aqueous single-phase suspended vehicle containing 20% by weight to about 60% by weight of solvent and about 80% to about 40% by weight of pyrrolidone polymer and having a viscosity at 37 ° C. of 5000 to 50,000 poise;
Contains, here:
The solvent is at least one of lauryl lactate, lauryl alcohol, and benzyl benzoate;
The pyrrolidone polymer is polyvinylpyrrolidone;
30-90% by weight of the particle preparation is the insulin secretagogue peptide;
The ratio of the insulin secretagogue peptide of the particle preparation to the antioxidant and the sugar in weight% is 1/2 to 10/1; and the particle preparation is dispersed in the suspension vehicle;
A suspension product, characterized in that. The suspension preparation according to claim 1, wherein the insulin secretagogue peptide is exenatide. The suspension preparation according to claim 1, wherein the buffer is selected from at least one of citrate, histidine, succinate, and tris. The suspension preparation according to claim 1, wherein the sugar is sucrose. The suspension preparation according to claim 1, wherein the solvent is benzyl benzoate. The suspension preparation according to claim 1, wherein the antioxidant is at least one of methionine, ascorbic acid, sodium thiosulfate, ethylenediaminetetraacetic acid (EDTA), citric acid and butylated hydroxytoluene. The suspension preparation according to claim 1, wherein the particle preparation contains exenatide, sucrose, methionine and citric acid. The suspension preparation according to claim 1, wherein in the particle preparation, the weight% ratio of the insulin secretagogue peptide to the antioxidant and the sugar is 5/1 to 10/1. The suspension preparation according to claim 1, wherein the water content of the particle preparation is less than 5% by weight. A delivery device containing a suspension product, wherein the suspension product is as follows:
A particle formulation containing an insulin-promoting peptide, antioxidant, sugar and buffer, wherein the insulin-promoting peptide is at least one of exenatide, a derivative of exenatide and an analog of exenatide; and about. A non-aqueous single-phase suspended vehicle containing 20% by weight to about 60% by weight of solvent and about 80% to about 40% by weight of pyrrolidone polymer and having a viscosity at 37 ° C. of 5000 to 50,000 poise;
Contains, here:
The solvent is at least one of lauryl lactate, lauryl alcohol, and benzyl benzoate;
The pyrrolidone polymer is polyvinylpyrrolidone;
30-90% by weight of the particle preparation is the insulin secretagogue peptide;
The ratio of the insulin secretagogue peptide of the particle preparation to the antioxidant and the sugar in weight% is 1/2 to 10/1; and the particle preparation is dispersed in the suspension vehicle;
A delivery device, characterized in that. The delivery device according to claim 10, wherein the insulin secretagogue peptide is exenatide. 11. The delivery device of claim 11, wherein the buffer is selected from at least one of citrate, histidine, succinate, and tris. 11. The delivery device according to claim 11, wherein the sugar is sucrose. The delivery device according to claim 11, wherein the antioxidant is at least one of methionine, ascorbic acid, sodium thiosulfate, ethylenediaminetetraacetic acid (EDTA), citric acid and butylated hydroxytoluene. The delivery device according to claim 10, wherein the particle preparation contains exenatide, sucrose, methionine and citric acid. The delivery device according to claim 10 for treating type II diabetes in a subject in need of treatment, wherein the suspension from the delivery device at a substantially constant rate over a period of about 1 month to about 1 year. A delivery device to which a formulation is delivered. The delivery device according to claim 10 for reducing at least one of a subject's body weight, a subject's blood glucose concentration, and a subject's HbA1C level, substantially over a period of about 1 month to about 1 year. A delivery device in which the suspension product is delivered from the delivery device at a constant rate.

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